1. Field
The present disclosure relates to deimmuized anti c-Met humanized antibodies and pharmaceutical compositions including the same for the prevention or treatment of cancer.
2. Description of the Related Art
c-Met is a receptor of a hepatocyte growth factor (HGF). HGF is a kind of cytokine that binds to an extracellular site of c-Met receptor tyrosine kinase to induce division, movement, cytomorphosis, and vasculogenesis of various normal cells and tumor cells. c-Met is a typical receptor tyrosine kinase present on a cell surface and is a cancer-causing gene, and in some cases, independently from the ligand HGF, c-Met is involved in various mechanisms related to tumors, including cancer development, cancer transition, movement of cancerous cells, invasion of cancerous cells, and neovasculogenesis. Thus, c-Met is gaining attention as an anti-cancer target.
In particular, overexpression of c-Met may contribute to the development of resistance to anti-cancer drugs, such as Erbitux™, Tarceva™, and Herceptin™ Erbitux™ and Tarceva™ are anti-cancer drugs that target EGFR (ERBB1) and act by blocking transmittance of signals associated with cancer generation mechanisms. Herceptin™ is a breast cancer drug that targets ERBB2 (HER2) and blocks transmittance of signals for the proliferation of cells. Accordingly, c-Met has become a target molecule for anti-cancer drugs.
The AbF46 antibody is an c-Met specific antibody generated through mouse immunization. This mouse-derived antibody may cause immunogenicity, such as an anti-isotypic reaction, when administered to humans for therapeutic purposes, so various antibody engineering technologies have been developed to prevent immunogenicity. Chimeric antibodies are manufactured by substituting a constant region that may cause an anti-isotypic reaction with a constant region of a human antibody through genetic engineering. Examples of chimeric antibodies manufactured using this antibody engineering method are Basiliximab™ (Simulect; IgG1 anti-CD25, Norvatis) and Cetuximab™ (Erbitux; IgG1 anti-EGFR, ImClone). However, clinical trial results showed the occurrence of a human anti-chimeric antibody reaction (HACA).
As described above, chimeric antibodies have been substantially improved compared to mouse antibodies in terms of anti-idiotypic reaction, but, mouse-derived amino acids are still present in variable regions and thus, side effects with respect to a potential anti-idiotypic reaction may occur. As an antibody engineering method for resolving this problem, a humanized antibody production technology has been developed. However, even when complementarity determining regions (CDR) are drafted on an optimized human antibody framework, an amino acid affecting antigen binding may be present on a mouse antibody framework, so that the antigen binding may not be preserved. Accordingly, an additional antibody engineering technology for restoring antigen binding is necessary. Among novel antibody medicines that are commercially available following the approval of the U.S. food and drug administration, humanized antibodies overwhelmingly dominate the market compared to mouse or chimeric antibodies, and Herceptin™ (Genentech), which is a breast cancer drug, shows a very low level of about 0.1% of anti-human antibody reaction in clinical trials.
Accordingly, there is a need to develop a humanized antibody of mouse anti c-Met antibody that has minimized immunogenicity and can enter previous-phase clinical trials.